Purpose.The National Institutes of Health (NIH) announces a
unique opportunity for investigators working with molecular probe compounds to
gain access to a robust ‘virtual pharma’ drug development network to develop neurotherapeutic
drugs. Successful applicants to this initiative will be collaborative
participants in this network, receiving both funding and no-cost access to
contracted drug development services that are not typically available to the
NIH-funded research community. Funding will be provided through a U01
cooperative agreement to conduct biological testing of compound analogs in
disease assays and models in the investigator’s laboratory. No-cost drug
development services will also be provided, including medicinal chemistry
optimization, IND-directed pharmacology and toxicology, and Phase I clinical
testing. Researchers who have disease assays and small molecule compounds that
show promise for treating nervous system and psychiatric disorders, but that
are not yet suitable for clinical testing, are strongly encouraged to apply. Investigators
funded through this FOA will be active partners in the design and
implementation of the drug development strategy in collaboration with an
NIH-appointed advisory panel of drug development experts. This program is
structured to allow investigators to maintain control of the intellectual
property generated using their assays and starting compounds and to pursue
commercialization of compounds that are developed within the program. This
program was established by the NIH Blueprint for Neuroscience and will consider
applications for nervous system disorders within the missions of any of the 16
participating NIH Institutes (http://neuroscienceblueprint.nih.gov/blueprint_basics/about_blueprint.htm). Disorders of interest include, but are
not limited to, neurological, psychiatric and developmental disorders, dementias
of aging, diseases and disorders of the eye or ear, and drug and alcohol
dependence and addiction. By initiating development of up to 20 new
small-molecule compounds over two years, we anticipate that approximately four
compoundswill enter Phase 1 clinical trials within
this program. The ultimate goals of this Neurotherapeutics Grand Challenge are
to produce at least one novel and effective drug for a nervous system disorder
that is currently poorly treated and to catalyze industry interest in novel
disease targets by demonstrating early-stage success.

Mechanism of Support. This FOA will use the NIH Research Project Cooperative Agreement (U01)
award mechanism.

Funds Available and Anticipated Number
of Awards.The
participating ICs intend to commit up to $1,750,000 in FY 11 to fund up to 10
awards in the first year of this program. Awards issued under this FOA are
contingent upon the availability of funds and the submission of a sufficient
number of meritorious applications. It is anticipated that funded projects
will carry direct costs of up to $125,000 per year for in vitro and/or in vivo
bioactivity screening.

Budget
and Project Period. Project duration can be up to five
years; budgets should be appropriate for the proposed work. The actual
duration of individual projects will depend on successful achievement of
milestones as described in this FOA.

Application
Research Strategy Length:The U01 Research
Strategy section may not exceed 12 pages, including
tables, graphs, figures, diagrams, and charts. See Table of Page
Limits.

Institutions/Organizations.Institutions/organizations listed in Section
III, 1.A. are eligible to apply.

Eligible Project
Directors/Principal Investigators (PDs/PIs). Individuals
with the skills, knowledge, and resources necessary to carry out the
proposed research are invited to work with their institution/organization
to develop an application for support. Individuals from underrepresented
racial and ethnic groups as well as individuals with disabilities are
always encouraged to apply for NIH support.

Number
of PDs/PIs. More than one PD/PI (i.e., multiple
PDs/PIs), may be designated on the application.

Number
of Applications.Applicants
may submit more than one application, provided they are scientifically distinct.

Resubmissions. Resubmission applications are not permitted in
response to this FOA.

Renewals. Renewal applications are not permitted in response
to this FOA.

The NIH Blueprint for Neuroscience Research established
the Grand Challenge for Neurotherapeutics in response to the paucity of
effective treatments for disorders of the nervous system. This program intends
to develop drugs successfully through clinical Phase I and facilitate industry
partnerships for their full development. The long-term goal of this grand
challenge is to produce at least one novel and effective medication for a disorder
of the nervous system that is currently poorly treated or untreatable.

Most promising compounds identified through basic
research are not sufficiently drug-like for human testing. Before a new
chemical entity can be tested in a clinical setting, it must undergo a process
of chemical optimization to improve potency, activity and drug-likeness and
pre-clinical safety testing to meet the standards set by the Food and Drug
Administration (FDA) for clinical testing. These activities are largely the
domain of the pharmaceutical industry and contract research organizations, and
the necessary expertise and resources are not commonly available to basic
researchers. To address this problem, the NIH Blueprint for Neuroscience
Research is establishing a ‘virtual pharma’ network of contract service
providers and consultants with extensive industry experience to enable drug
development in the NIH neuroscience research community. This Funding
Opportunity Announcement (FOA) is soliciting applications for U01 cooperative
agreement awards from investigators with small molecule compounds that have potential
for development into clinical candidates within this network.

This FOA and the Blueprint Neurotherapeutics ‘virtual
pharma’ network is an initiative of the NIH Blueprint for Neuroscience
Research, which provides a framework for collaborative activities involving
sixteen participating NIH Institutes, Centers, and Offices that support
research on the nervous system (http://neuroscienceblueprint.nih.gov/blueprint_basics/about_blueprint.htm). By pooling resources and expertise,
the NIH Blueprint for Neuroscience Research takes advantage of economies of
scale, confronts challenges too large for any single Institute or Center, and
develops research tools and infrastructure that serve the entire neuroscience
community.

B. Research Scope

I. Introduction

To be accepted into the network, applicants to this FOA
must have in hand the starting compounds for chemical optimization and
bioactivity assays for testing new analog compounds generated through the
Blueprint Neurotherapeutics drug development network (see Entry Criteria below
for more details). Successful applicants under this FOA will receive 1) funding
for biological assessment of compounds in their laboratories and 2) no-cost access
to drug development resources that typically reside in the pharmaceutical
industry, including iterative medicinal chemistry optimization, pharmacokinetics,
toxicology, manufacture and formulation, and Phase I clinical safety testing. The
budget of the U01 application will support only the work in investigators’
laboratories, which will involve testing of compounds in biological assays and
models related to the target disorder.

Each drug development project will be directed by a
collaborative Lead Development Team, co-chaired by the U01 investigator and a
consultant with extensive industry expertise identified and supported by the
NIH Blueprint for Neuroscience Research. The team will also include consultants
with additional expertise, supported by NIH, and NIH staff. Strategic decisions
will be made by this team, with oversight from the Blueprint Neurotherapeutics Steering
Committee and, ultimately, the NIH Blueprint for Neuroscience Research Institute
and Center Directors.

This program is structured to allow U01 awardee
institutions to retain ownership of intellectual property for compounds
developed within the network.

II. Entry Criteria

To be considered responsive to this announcement,
applicants must have in hand at least one small-molecule compound with
well-demonstrated bioactivity that can be further developed as a drug for a
disease or disorder of the nervous system. Applicants must also be able to
conduct bioactivity and efficacy testing to assess compounds synthesized in the
development process and provide all pre-clinical validation for the target
disorder. Entry criteria for these compounds and assays are detailed below.

1. Entry Criteria for Compounds

To participate in this program, applicants must have in
hand well-characterized bioactive small-molecule compounds that can provide a
starting point for medicinal chemistry optimization. This program is not
designed to support biologics development. Applications may propose development
of more than one chemical scaffold showing the desired profile of activity
against the target of interest. Although it is desirable to have some knowledge
of chemical structure activity relationships (SAR) at the target of interest,
individual active compounds that are well-characterized biologically are also
appropriate for this program. Compounds proposed for entry into the Blueprint
Neurotherapeutics network should possess the following attributes:

Activity in a primary assay. Activity in a primary screening assay
should be confirmed by repeat dose-response testing. For biochemical assays,
compounds should generally show activity at 1µM
or below. For cell-based assays, compounds should ideally show activity at 10µM or below.

Activity in secondary/confirmatory assay(s). Activity must be confirmed in at least
one secondary assay relevant to the target disorder.

Cellular activity. Compounds should be active in at least one cell-based
assay. An IC50 or EC50 of <10µM is desirable.

In vivo efficacy. Efficacy in an in vivo model of the relevant disorder or
disease is desirable but not required.

Determination of identity and purity. The starting compound(s) should have
proof of identity and purity (typically >90%, as determined by, e.g., NMR,
melting point, or LC/MS) and biological activity should have been demonstrated
with more than one batch of compound.

Compound target selectivity. In cases where the molecular target of
compound action is known, the applicant should demonstrate the degree of
selectivity for the intended target over closely related targets. Counter-screening
to determine selectivity across a broad panel of unrelated pharmacological
targets (e.g., G protein-coupled receptors, kinases, etc.) is desirable, but
not required.

Structure-activity relationship (SAR). Demonstration that chemical analogs of
a proposed compound show similar biological activity is desirable. Limited SAR
information may have been derived from activity of analogs in a screening
library or from testing of commercially available analogs.

2. Entry Criteria for Bioactivity Assays

This initiative is not intended to support development of
new assays, thus the applicant must propose the use of existing, well characterized
assays and models. Assays that do not meet all entry criteria may undergo
validation as an early stage of the U01, if necessary. However, proposed
primary screening assays should be sufficiently well developed and
characterized to demonstrate feasibility for validation and use in a medicinal
chemistry SAR effort within one year of the start of the award.

Applicants should have three types of assays in hand: 1) a
moderate throughput primary screening assay, 2) one or more secondary assays
for confirmation of activity and potential efficacy and 3) counter screening
assays for target selectivity, where necessary. For each type of assay, the
parameters that should be discussed in the application are outlined below.

Primary screening assay. This must be an assay with moderate
throughput or better, e.g., a reporter assay, which will be used to perform
routine weekly screening of compounds synthesized for iterative medicinal
chemistry. To inform the medicinal chemistry design, the assay must be
sufficiently robust and reproducible to reliably rank compounds with similar
activities. Ultimately, the primary screening assay should meet the following
criteria. If these criteria are not already demonstrated for the assay when the
application is submitted, the application should include data and discussion to
support the feasibility of achieving this level of assay validation within the
first year of the award.

A statistical demonstration of reliability,
e.g., a Z’ score =0.5 and a coefficient of variation (CV) =20%

A reproducible demonstration of dose-response
with a positive control compound over at least 3 orders of magnitude (e.g.,
0.1-10µM)

Throughput of 20-40 compounds per 1-2 weeks,
run with sufficient replicates to produce robust and reproducible 10-point
dose-response curves.

Secondary confirmation assays. The applicant must have one or more
secondary assays with sufficient biological validation to confirm the activity
of compounds identified in the primary assay and demonstrate potential efficacy
in the target disorder. These may be low to moderate throughput assays.
Ideally, at least one secondary assay would be capable of generating
dose-response data for multiple compounds simultaneously. The application should
contain the following information about secondary screening assays:

Relevance to intended biological drug target
and disease

Throughput and cycle time of each

Potential to generate dose response data

Reproducibility of the assay with positive control
compounds

Selectivity and counter-screening assays. Where the molecular target of drug
action is known, e.g., a particular kinase, it may bear similarity to other
cellular targets. In these cases, the applicant should describe criteria for
compound specificity for these targets and screening assays to determine that
specificity. Where aspects of the screening approach are prone to unwanted
activities or artifact, counter screens should be available to rule out these
unwanted activities. Counter-screening and selectivity assays should have demonstrated
reliability and adequate throughput for their proposed use in the development
program.

III. Timeline of Drug Development in the Network and the
U01 Investigator’s Role

Directing compounds through the drug development pipeline
will be a collaborative effort. After award, each successful applicant will
work closely with NIH staff and drug development consultants to finalize a drug
development plan involving the Blueprint Neurotherapeutics Network contractors.
This plan will define activities and advancement criteria for a series of
stages through which compounds will progress during development. This section
outlines the stages and timeline of work that will be conducted throughout the
development pipeline, beginning with the entry of a well-characterized hit
compound and ending with a novel candidate drug with demonstrated safety in
humans. This section also outlines the roles of the NIH Blueprint
Neurotherapeutics Network and the U01 investigator in each stage of the
pipeline. In conjunction with the Generic Project Timeline at: http://neuroscienceblueprint.nih.gov/bpdrugs/apply.htm, this section can be used as a guide to develop the budget for the U01
application, which should include only the activities that will be conducted in
the investigator’s laboratory. Activities supported by Blueprint
Neurotherapeutics contracts, such as chemistry, pharmacology, toxicology,
regulatory activities and clinical testing, should not be included in the U01
application budget.

1. Exploratory chemisty/feasibility (for budget purposes,
assume 6 months). Each
project will undergo a feasibility phase in which investigators will validate
their primary screening assays for SAR studies and test a collection of
approximately 50-100 chemical compound analogs. These will be primarily
identified from commercial sources and supplied to the investigator by NIH
Blueprint Neurotherapeutics contractors. Work in this phase will be directed
toward determining whether the compounds and assays are amenable to medicinal
chemistry optimization.

2. Medicinal chemistry optimization (for budget purposes,
assume 2 years). If the outcomes of the feasibility studies are successful, compounds will enter
a full-scale, iterative medicinal chemistry optimization phase to improve
bioactivity, potency and pharmacological properties. This process of
understanding the structure activity relationship (SAR) between the compounds
and the desired drug properties typically requires dozens of rounds of compound
synthesis and testing. The ultimate goal of the SAR effort is selection of a
pre-clinical candidate compound with sufficient bioactivity and drug-likeness
to proceed to IND-directed pre-clinical safety assessment.

During this stage, a Lead Development Team will be formed
to collaboratively manage and coordinate the progress of compounds through the
development pipeline. The team will be co-chaired by the U01 investigator and a
drug development consultant identified and supported by the Blueprint
Neurotherapeutics program. The team will include other consultants as needed at
each stage of the project to advise on chemistry, biology and Absorption,
Distribution, Metabolism, Excretion and Toxicity (ADMET) study design and
interpretation.

The major role of the U01-funded investigator in this
process is to conduct primary biological assessment of compounds on a regular,
one-to-two week schedule to inform the design of subsequent iterations of
compound synthesis. In addition to a regular testing schedule in the primary
assay, the PI will provide confirmation of the activity of select compounds in
secondary assays and possibly animal models relevant to the drug target.

NIH Blueprint Neurotherapeutics contractors will produce
compound analogs for SAR testing and provide standard screening services to
assess in vitro and in vivo ADMET characteristics of the compounds.

In the first year, medicinal chemistry will be in a
‘hit-to-lead’ phase, focusing heavily on optimizing activity and potency of
compounds in the primary and secondary disease assays. In the subsequent ‘lead
optimization’ phase, SAR will increase emphasis on ADMET properties of the
compounds, with continued monitoring and optimization of bioactivity. If
compound testing in in vivo animal models is proposed, this should be limited
to testing a small number of selected advanced compound analogs (e.g., 3) in
year 3.

3. IND-enabling studies (for budget purposes, assume 1.5
years). If a
therapeutic candidate is identified which meets the target criteria for activity,
efficacy, and favorable physicochemical and ADMET properties, it will move into
IND-directed pharmacology and toxicology studies. Blueprint Neurotherapeutics
contractors, with direction from the Lead Development Team, will conduct the
preclinical safety studies, GMP synthesis, formulation and other activities
required to ready a compound for human testing. Blueprint Neurotherapeutics
contractors will provide data and reports in a format suitable for inclusion in
an IND application and will assist in the development of the application. The U01
investigator will be responsible for the submission of the IND application and scheduling
meetings with the FDA.

4. Phase I clinical trial(for budget purposes, assume 1
year). Once an IND has been submitted successfully to the FDA, a Phase I
clinical trial, typically in healthy volunteer subjects, will be conducted by a
Blueprint Neurotherapeutics contractor. The development of the protocol and
conduct of the trial will involve input from a Clinical Development Team, which
will include the U01 investigator, clinical consultants identified by the NIH,
and Blueprint Neurotherapeutics staff. Costs associated with the conduct of
clinical trials will be supported outside the U01 and should not be included in
the requested budget. In most cases, Phase I human studies will be conducted
under a contract in the NIH Blueprint Neurotherapeutics Network.

IV. Milestones

Because drug development is an inherently high-risk
process, it is anticipated that there will be a significant attrition rate as
projects move through the pipeline. Go/No-Go milestones will be agreed upon at
the start of each project and, in consultation with the Lead Development Team,
investigators will produce milestone progress reports for independent evaluation
by the Blueprint Neurotherapeutics Steering Committee.

If a funded project does not make sufficient
progress toward the agreed upon milestones at any stage, funding for the
project and access to Blueprint Neurotherapeutics contract resources may be discontinued
unless an additional source of funding is identified.

V. Projects Not Responsive to this Announcement:

PIs that are seeking only funding for drug
development and have sufficient access to medicinal chemistry and drug
development expertise should consider funding programs available through the
individual NIH Institutes. Please contact program staff at the relevant
Institute for information about available drug development programs for
specific disorders.

Projects requiring only access to IND-directed
preclinical testing for compounds that have already undergone medicinal
chemistry optimization are not suitable for this program. The NIH Rapid Access
toInterventional Development (NIH-RAID) Program(www.nihroadmap.nih.gov/raid) offers investigators access to IND-directed
services on a competitive basis.

Development of biomarkers will not be
supported through this program. Please contact program staff at the appropriate
Institute for funding opportunities for biomarker development.

Research aims appropriate for an
investigator-initiated R01 grant, such as understanding underlying biological
mechanisms of disease, should not be included in an application under this FOA.

C. Instructions to Applicants

An application to this FOA should address the points
raised below.

Significance:

Disease of interest: Describe the current state of knowledge of the disease
etiology, clinical characteristics, and current and projected disease
prevelance. Briefly discuss available treatments and their limitations. Provide
a brief overview of the state of clinical trials research in this disease area,
including relevant clinical outcome measures and biomarkers. Describe the
clinical feasibility of the target disorder, for example, the availability of
clinical trials networks and sites for later-phase clinical trials, and
identify any clinical collaborators for this project.

Drug Target: Describe the intended molecular or cellular drug target.
Provide evidence for a role of the target in disease pathophysiology, target
validation, druggability, and novelty of the target with respect to ongoing
biopharma development programs or existing drugs. Describe the expected
clinical impact that a drug directed against this target might have on the
features of disease and disease progression, e.g., whether the intervention is
expected to be palliative or disease-modifying. Indicate whether there are reliable
biomarker(s) available to monitor effects on the target in a clinical or pre-clinical
setting. Indicate whether a drug must cross the blood brain barrier to
successfully impact this target.

Summary of Key Drug Characteristics: Include a table of key properties for
the intended drug (see guidance and table template at: http://neuroscienceblueprint.nih.gov/bpdrugs/apply.htm,
including the intended disorder, patient population, mode, duration and
frequency of delivery, and standards for efficacy.

Approach:

In addition to at least one small molecule compound
proposed for development, the applicant must provide data demonstrating the
suitability of the intended primary and confirmatory assays and models for drug
development.

Small molecule compounds proposed for development: Applicants should address the compound
entry criteria outlined in the Research Scope section of the FOA.
Applicants may propose the development of more than one chemical scaffold
showing the desired profile of activity against the target of interest.
Describe the evidence for activity of the compounds(s) on the target and
disease of interest. Describe the level of activity and potency (EC50 or IC50) of the compounds in biochemical and cellular bioassays and
the in vitro toxicity (LD50). In addition to chemical structures,
information should be provided on known chemical and physical characteristics
of the compound(s), e.g., drug-like properties, solubility, chemical
liabilities, etc. Present the results of testing any chemical analogs and
inferences about structure activity relationships (SAR).

Proposed primary and secondary assays: Describe the primary assay that will
be used to inform chemical SAR studies. Provide justification for the
relationship of the primary assay to the disease target. Present data to
support validation of the assay for reproducible ranking of similarly active
compounds based on activity and potency, addressing the assay entry criteria
outlined in section B.II of the Funding Opportunity Description above. If the
primary assay is not fully validated when the application is submitted, discuss
the feasibility of achieving these entry criteria within the first year of the
award.

Identify secondary and confirmatory assays and models (in
vitro and in vivo) for preclinical bioactivity validation of optimized
compounds. Describe the degree of pre-clinical or clinical validation of each
assay and model for the disease of interest and the relevance of each to the
proposed target of drug action. Provide data to demonstrate the correspondence
between results of the primary and secondary assays.

Approach for use of primary and secondary assays: Summarize methods for the primary and
secondary assays proposed for compound optimization, including methods for ongoing
internal quality control, data analysis and plans for routine submission of
data to a centralized Blueprint Neurotherapeutics database. The application
should include a Summary Table of Bioactivity Assays (see table template
at: http://neuroscienceblueprint.nih.gov/bpdrugs/apply.htm) proposed for evaluating
the clinical promise of compounds, indicating the throughput for each assay and
advancement criteria for progressing compounds from one assay to the next. Describe
any potential pitfalls associated with the use of the primary and secondary
assays and approaches to their resolution.

Management plan: Describe the roles and extent of participation of key
personnel over the course of the small molecule development process, from
compound optimization through Phase I clinical trials. Indicate the willingness
of the Principal Investigator and key personnel to operate under the
cooperative agreement terms and conditions outlined in section VI.2.A of the
FOA. If needed, describe the availability of a clinical consultant with
expertise in the target disorder. Clinical experts should be sought as needed
to develop the application (e.g., to determine the Summary of Key Drug
Characteristics: http://neuroscienceblueprint.nih.gov/bpdrugs/apply.htm),
and available after award to aid in determining the goals of the drug
development program and to consult on the design of the clinical trial.

Resources: (Note that this is a separate section of the
application from the Research Strategy section).

Intellectual property considerations for small molecule
compounds proposed for development: Applicants should describe any constraints that they are
or may be aware of that would impede use or development of the compound(s) in
achieving the program goals (e.g., certain restrictions under transfer or
sharing agreements, applicant’s previous or present intellectual property filings
and publications).

Intellectual property considerations for primary and
secondary assays: Applicants should describe any constraints that they are or may be aware of
that would impede use of the assays and models for research purposes and/or
commercial development.

Intellectual property management and commercialization: Applicants should describe their
institutions’ existing or planned infrastructure for bringing the compounds to
practical application (e.g., licensing for further drug development, managing
intellectual property, commercializing discoveries) consistent with achieving
the program goals For a multiple-PI, multiple-institution application,
applicants should describe the infrastructure of each institution for bringing
the technologies to practical application and for coordinating these efforts
(e.g., licensing, managing intellectual property) among the institutions
consistent with achieving the goals of the program.

This funding opportunity
will use a cooperative agreement award mechanism. In
the cooperative agreement mechanism, the Project Director/Principal
Investigator (PD/PI) retains the primary responsibility and dominant role for
planning, directing, and executing the proposed project, with NIH staff being
substantially involved as a partner with the Principal Investigator, as
described under the Section VI. 2. Administrative
Requirements,
"Cooperative Agreement Terms and Conditions of Award".

2. Funds Available

The
participating ICs intend to commit up to $1,750,000 in FY 11 to fund up to 10
awards in response to this FOA. It is anticipated that applications will carry
direct costs of up to $125,000 per year for in vitro and/or in vivo screening
of targets.

The estimated amount of funds available for support ofup to 10projects awarded as a result of
this announcement is $1,750,000 for
fiscal year 2011. Future year amounts will depend on annual
appropriations.

Because the nature
and scope of the proposed research will vary from application to application,
it is anticipated that the size and duration of each award will also vary.
Although the financial plans of the IC(s) provide support for this program,
awards pursuant to this funding opportunity are contingent upon the
availability of funds and the receipt of a sufficient number of meritorious
applications.

Facilities and
administrative costs requested by consortium participants are not included in
the direct cost limitation, see NOT-OD-05-004.

NIH
grants policies as described in the NIH Grants Policy Statement will apply to the
applications submitted and awards made in response to this FOA.

Any
individualwith the skills, knowledge, and resources necessary to
carry out the proposed research as the PD/PI is invited to work with his/her
institution to develop an application for support. Individuals from
underrepresented racial and ethnic groups as well as individuals with disabilities
are always encouraged to apply for NIH program support.

More than one PD/PI, or
multiple PDs/PIs, may be designated on the application for projects that
require a “team science” approach and therefore clearly do not fit the
single-PD/PI model. Additional
information on the implementation plans, policies and procedures to formally
allow more than one PD/PI on individual research projects is available at http://grants.nih.gov/grants/multi_pi.All PDs/PIs must be
registered in the NIH eRA Commons prior to the submission of the application
(see http://grants.nih.gov/grants/ElectronicReceipt/preparing.htm for instructions).

The decision of whether to
apply for a grant with a single PD/PI or multiple PDs/PIs is the responsibility
of the investigators and applicant organizations, and should be determined by
the scientific goals of the project. Applications for grants with multiple
PDs/PIs will require additional information, as outlined in the instructions
below. When considering multiple PDs/PIs, please be aware that the structure
and governance of the PD/PI leadership team as well as the knowledge, skills
and experience of the individual PDs/PIs will be factored into the assessment
of the overall scientific merit of the application. Multiple PDs/PIs on a
project share the authority and responsibility for leading and directing the
project, intellectually and logistically. Each PD/PI is responsible and
accountable to the grantee organization, or, as appropriate, to a collaborating
organization, for the proper conduct of the project or program, including the
submission of required reports. For further information on multiple PDs/PIs,
please seehttp://grants.nih.gov/grants/multi_pi.

Applications must have a D&B Data Universal
Numbering System (DUNS) number as the universal identifier when applying for
Federal grants or cooperative agreements. The D&B number can be obtained by
calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should
be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must
be typed in item (box) 2 only of the face page of the application form and the
YES box must be checked.

Every effort should be made to comply with the
format specifications, which are based upon a standard U.S. paper size of 8.5” x 11” within each PDF.

Funds for up to 8% Facilities and Administrative
(F&A) costs (excluding equipment) may be requested. SeeNOT-OD-01-028, March 29,
2001.

Organizations must comply with Federal/NIH
policies on human subjects, animals, and biohazards.

Organizations must comply with Federal/NIH
biosafety and biosecurity regulations. See Section VI.2., “Administrative and
National Policy Requirements”

Proposed research should provide special
opportunities for furthering research programs through the use of unusual
talent, resources, populations, or environmental conditions in other countries
that are not readily available in the United States or that augment existing U.S. resources.

Applications
with Multiple PDs/PIs

When multiple PD/PIs are
proposed, use the Face Page-Continued page to provide items 3a – 3h for all
PD/PIs. NIH requires one PD/PI be designated as the “contact PD/PI” for all
communications between the PD/PIs and the agency. The contact PD/PI must meet
all eligibility requirements for PD/PI status in the same way as other PD/PIs,
but has no special roles or responsibilities within the project team beyond
those mentioned above. The contact PD/PI may be changed during the project
period. The contact PD/PI should be listed in block 3 of Form Page 1 (the Face
Page), with all additional PD/PIs listed on Form Page 1-Continued. When
inserting the name of the PD/PI in the header of each application page, use the
name of the “Contact PD/PI, et. al.” The contact PD/PI must be from the
applicant organization if PD/PIs are from more than one institution.

All individuals designated
as PD/PI must be registered in the eRA Commons and must be assigned the PD/PI
role in that system (other roles such as SO or IAR will not give the PD/PI the
appropriate access to the application records). Each PD/PI must include their
respective eRA Commons ID in the eRA Commons User Name field.

Multiple
PD/PI Leadership Plan: For applications designating multiple PDs/PIs, the
section of the Research Plan entitled “Multiple PD/PI Leadership Plan”, must be
included. A rationale for choosing a multiple PD/PI approach should be
described. The governance and organizational structure of the leadership team
and the research project should be described, and should include communication
plans, process for making decisions on scientific direction, and procedures for
resolving conflicts. The roles and administrative, technical, and
scientific responsibilities for the project or program should be delineated for
the PDs/PIs and other collaborators.

If
budget allocation is planned, the distribution of resources to specific
components of the project or the individual PDs/PIs should be delineated in the
Leadership Plan. In the event of an award, the requested allocations may be
reflected in a footnote on the Notice of Award.

Prospective
applicants are asked to submit a letter of intent that includes the following
information:

Descriptive title of proposed research

Name, address, and telephone number of
the Principal Investigator

Names of other key personnel

Participating institutions

Number and title of this funding
opportunity

Although a letter of
intent is not required, is not binding, and does not enter into the review of a
subsequent application, the information that it contains allows IC staff to
estimate the potential review workload and plan the review.

Applications must be
prepared using the forms found in the PHS 398 instructions for preparing a
research grant application. Submit a signed, typewritten original of the
application, including the checklist, and three signed photocopies in one package to:

Applications must be received
on or before the application receipt date described above (Section
IV.3.A.). If
an application is received after that date, the application may be delayed in
the review process or not reviewed. Upon receipt, applications will be
evaluated for completeness by the CSR and for responsiveness by the reviewing
Institute. Incomplete and/or non-responsive applications will not be reviewed.

The NIH will not
accept any application in response to this funding opportunity that is
essentially the same as one currently pending initial review, unless the
applicant withdraws the pending application. However, when a previously
unfunded application, originally submitted as an investigator-initiated
application, is to be submitted in response to a funding opportunity, it is to
be prepared as a NEW application. That is, the application for the funding
opportunity must not include an Introduction describing the changes and
improvements made, and the text must not be marked to indicate the changes from
the previous unfunded version of the application.

All NIH awards
are subject to the terms and conditions, cost principles, and other
considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at NIH Grants Policy
Statement.

Pre-award costs are allowable. A grantee may, at its
own risk and without NIH prior approval, incur obligations and expenditures to
cover costs up to 90 days before the beginning date of the initial budget
period of a new award if such costs: 1) are necessary to conduct the project,
and 2) would be allowable under the grant, if awarded, without NIH prior
approval. If specific expenditures would otherwise require prior approval, the
grantee must obtain NIH approval before incurring the cost. NIH prior approval
is required for any costs to be incurred more than 90 days before the beginning
date of the initial budget period of a new award.

The incurrence
of pre-award costs in anticipation of a competing or non-competing award
imposes no obligation on NIH either to make the award or to increase the amount
of the approved budget if an award is made for less than the amount anticipated
and is inadequate to cover the pre-award costs incurred. NIH expects the
grantee to be fully aware that pre-award costs result in borrowing against
future support and that such borrowing must not impair the grantee's ability to
accomplish the project objectives in the approved time frame or in any way
adversely affect the conduct of the project (see NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.)

6. Other Submission Requirements

For
cooperative agreements, awardees must agree to the "Cooperative Agreement
Terms and Conditions of Award" in Section VI.2.A "Award
Administration Information".

PHS398 Research Plan Sections

All
application instructions outlined in the PHS398 Application Instructions are to
be followed, with the following additional requirements:

Specific
Aims is limited to 1 page.

Research
Strategy, including tables, graphs, figures, diagrams, and charts is limited to 12 pages. See Table of Page Limits.

Do not use
the Appendix to circumvent the page limitations. An application that does not
observe the required page limitations may be delayed in the review process.

Resource Sharing
Plan(s)

NIH considers the sharing of unique research resources developed through
NIH-sponsored research an important means to enhance the value and further the
advancement of the research. When resources have been developed with NIH funds
and the associated research findings published or provided to NIH, it is
important that they be made readily available for research purposes to
qualified individuals within the scientific community. If the final data/resources are not amenable to sharing,
this must be explained in the Resource Sharing section of the application (see http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm.)

All foreign applicants must complete and submit budget requests
using the Research & Related Budget component found in the application
package for this FOA. SeeNOT-OD-06-096.

Section
V. Application Review Information

1. Criteria

Only the review
criteria described below will be considered in the review process.

2. Review and Selection Process

Review Process

Applications
that are complete and responsive to the FOA will be evaluated for scientific and
technical merit by an appropriate peer review group convened by NINDS and in accordance with NIH peer review procedures (http://grants1.nih.gov/grants/peer/), using the review criteria
stated below.

As part of the scientific peer
review, all applications will:

Undergo
a selection process in which only those applications deemed to have the
highest scientific and technical merit, generally the top half of
applications under review, will be discussed and assigned an
impact/priority score.

Receive
a written critique.

Receive
a second level of review by the National
Advisory Councils of the 16 NIH Blueprint ICs.

The mission
of the NIH is to support science in pursuit of knowledge about the biology and
behavior of living systems and to apply that knowledge to extend healthy life
and reduce the burdens of illness and disability. As part of this
mission, applications submitted to the NIH for grants or cooperative agreements
to support biomedical and behavioral research are evaluated for scientific and
technical merit through the NIH peer review system.

Overall Impact

Reviewers
will provide an overall impact/priority score to reflect their assessment of
the likelihood for the project to exert a sustained, powerful influence on the
research field(s) involved, in consideration of the following five scored
review criteria, and additional review criteria (as applicable for the project
proposed).

Scored Review Criteria

Reviewers
will consider each of the five review criteria below in the determination of
scientific and technical merit, and give a separate score for each. An
application does not need to be strong in all categories to be judged likely to
have major scientific impact. For example, a project that by its nature
is not innovative may be essential to advance a field.

Significance. Does the project address an important problem or a critical
barrier to progress in the field? If the aims of the project are
achieved, how will scientific knowledge, technical capability, and/or clinical
practice be improved? How will successful completion of the aims change
the concepts, methods, technologies, treatments, services, or preventative
interventions that drive this field?

Investigator(s). Are the PD/PIs, collaborators, and other researchers well suited
to the project? If Early Stage Investigators or New Investigators, or in
the early stages of independent careers, do they have appropriate experience
and training? If established, have they demonstrated an ongoing record of
accomplishments that have advanced their field(s)? If the project is
collaborative or multi-PD/PI, do the investigators have complementary and
integrated expertise; are their leadership approach, governance and
organizational structure appropriate for the project? Recognizing that the NIH does not require the applicant to
have drug development expertise, is the experience with biological testing
sufficient to support and inform a drug development effort? Is there access to
clinical expertise necessary to define the goals of a drug development effort
in the target disorder?

Innovation. Does the application challenge and seek
to shift current research or clinical practice paradigms by utilizing novel
theoretical concepts, approaches or methodologies, instrumentation, or
interventions? Are the concepts, approaches or methodologies,
instrumentation, or interventions novel to one field of research or novel in a
broad sense? Is a refinement, improvement, or new application of
theoretical concepts, approaches or methodologies, instrumentation, or
interventions proposed?Is the drug target novel
among ongoing drug development programs in industry and academia, regardless of
perceived market value?

Approach. Are the overall strategy, methodology, and analyses well-reasoned
and appropriate to accomplish the specific aims of the project? Are
potential problems, alternative strategies, and benchmarks for success
presented? If the project is in the early stages of development,
will the strategy establish feasibility and will particularly risky aspects be
managed?
If the project involves clinical research, are the plans for 1) protection of
human subjects from research risks, and 2) inclusion of minorities and members
of both sexes/genders, as well as the inclusion of children, justified in terms
of the scientific goals and research strategy proposed? Is the target disorder at an appropriate stage of
translational readiness for a drug development effort? Is there a compelling
biological rationale for the role of the proposed drug target in the disorder
of interest? Has the target been properly and appropriately validated, at least
at a pre-clinical stage? Is the Summary of Key Drug Characteristics appropriate
to the disorder? Is there clinical feasibility for testing a compound that
would emerge from the proposed effort? Recoginzing that NIH does not require a
proposal for an overall drug development strategy, is the proposed approach for
a biological testing scheme sufficient to provide complete pre-clinical assessment
of a candidate compound in the target disorder? Is the biological testing
strategy maximally efficient and feasible for a five-year development program?
Is the proposed primary screening assay suitable for a rapidly iterative
medicinal chemistry program? Do the starting compound(s) constitute a tractable
starting point for medicinal chemistry optimization? Are intellectual property
or patent issues explained in the application and approaches for navigating
these satisfactorily described?

Environment. Will the scientific environment in which the work will be done contribute
to the probability of success? Are the institutional support, equipment
and other physical resources available to the investigators adequate for the
project proposed? Will the project benefit from unique features of the
scientific environment, subject populations, or collaborative
arrangements?

Additional Review Criteria

As applicable
for the project proposed, reviewers will consider the following additional items in the determination of scientific and
technical merit, but will not give separate scores for these items.

Protections
for Human Subjects. For research that
involves human subjects but does not involve one of the six categories of
research that are exempt under 45 CFR Part 46, the committee will evaluate the
justification for involvement of human subjects and the proposed protections
from research risk relating to their participation according to the following
five review criteria: 1) risk to subjects, 2) adequacy of protection against
risks, 3) potential benefits to the subjects and others, 4) importance of the
knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research
that involves human subjects and meets the criteria for one or more of
the six categories of research that are exempt under 45 CFR Part 46, the
committee will evaluate: 1) the justification for the exemption, 2) human
subjects involvement and characteristics, and 3) sources of materials.

Inclusion
of Women, Minorities, and Children. When
the proposed project involves clinical research, the committee will evaluate
the proposed plans for inclusion of minorities and members of both genders, as
well as the inclusion of children.

Vertebrate
Animals. The committee will evaluate the
involvement of live vertebrate animals as part of the scientific assessment
according to the following five points: 1) proposed use of the animals, and
species, strains, ages, sex, and numbers to be used; 2) justifications for the
use of animals and for the appropriateness of the species and numbers proposed;
3) adequacy of veterinary care; 4) procedures for limiting discomfort,
distress, pain and injury to that which is unavoidable in the conduct of
scientifically sound research including the use of analgesic, anesthetic, and
tranquilizing drugs and/or comfortable restraining devices; and 5) methods of
euthanasia and reason for selection if not consistent with the AVMA Guidelines
on Euthanasia.For
additional information, see http://grants.nih.gov/grants/olaw/VASchecklist.pdf.

Biohazards. Reviewers will assess whether materials or procedures proposed are
potentially hazardous to research personnel and/or the environment, and if needed,
determine whether adequate protection is proposed.

Resubmission
Applications.Resubmission
applications are not permitted in response to this FOA.

Renewal Applications.Renewal applications are not permitted
in response to this FOA.

Revision
Applications. Revision applications are not permitted
in response to this FOA.

Additional Review Considerations

As applicable
for the project proposed, reviewers will address each of the following items,
but will not give scores for these items and should not consider them in
providing an overall impact/priority score.

Applications
from Foreign Organizations.
Reviewers will assess whether the project presents special opportunities for
furthering research programs through the use of unusual talent, resources, populations,
or environmental conditions that exist in other countries and either are not
readily available in the United States or augment existing U.S. resources.

Select
Agents Research. Reviewers will assess the information
provided in this section of the application, including 1) the Select Agent(s)
to be used in the proposed research, 2) the registration status of all entities
where Select Agent(s) will be used, 3) the procedures that will be used to
monitor possession use and transfer of Select Agent(s), and 4) plans for
appropriate biosafety, biocontainment, and security of the Select Agent(s).

A
formal notification in the form of a Notice of Award (NoA) will be
provided to the applicant organization. The NoA signed by the grants management
officer is the authorizing document. Once all administrative and programmatic
issues have been resolved, the NoA will be generated via email notification
from the awarding component to the grantee business official.

Selection of an application for award is not an
authorization to begin performance. Any costs incurred before receipt of the
NoA are at the recipient's risk. These costs may be reimbursed only to the
extent considered allowable pre-award costs. See Also Section
IV.5. Funding Restrictions.

The
following Terms and Conditions will be incorporated into the award statement
and will be provided to the Principal Investigator as well as to the
appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms
and Conditions of Award

The following special
terms of award are in addition to, and not in lieu of, otherwise applicable OMB
administrative guidelines, HHS grant administration regulations at 45 CFR Parts
74 and 92 (Part 92 is applicable when State and local Governments are eligible
to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and
funding instrument used for this program will be the cooperative agreement an
"assistance" mechanism (rather than an "acquisition"
mechanism), in which substantial NIH programmatic involvement with the awardees
is anticipated during the performance of the activities. Under the cooperative
agreement, the NIH purpose is to support and stimulate the recipients'
activities by involvement in and otherwise working jointly with the award
recipients in a partnership role; it is not to assume direction, prime
responsibility, or a dominant role in the activities. Consistent with this
concept, the dominant role and prime responsibility resides with the awardees
for the project as a whole, although specific tasks and activities may be
shared among the awardees and the NIH as defined below.

2.
A.1. Principal Investigator Rights and Responsibilities

The Principal Investigator
will have the primary responsibility for:

Determining experimental approaches, designing
protocols, conducting experiments, and analyzing and interpreting research data
related to the compound bioactivity testing funded through this U01.

Serving as Co-chair of the Project Lead
Development Team (LDT), participating in biweekly conference calls and annual
face-to-face meetings in the Washington, DC area.

With the LDT, assisting in the development of a project milestone plan
at the outset of the project.

Coordinating and participating with NIH
staff and NIH-contracted consultants in all aspects of scientific and technical
management of the project.

Collaborating and communicating effectively with
NIH service contractors to achieve project goals.

Providing goals and strategies for assay
validation, screening throughput, and quality control, to the NIH Program
Official as requested.

Ensuring that primary and secondary screening
data and assay protocols developed as a part of this project are deposited in a
centralized Blueprint Neurotherapeutics (BPN) database according to the
timeline agreed upon by the LDT and the NIH Program Official and according to
BPN policies.

Adhering to BPN policies, including those
regarding data release, intellectual property, and publications.

Implementing all scientific and policy decisions
approved by the LDT and the BPN program.

Submitting periodic milestone progress reports in
a standard format, as agreed upon by the LDT and BPN program.

Preparing for annual administrative site visits
by NIH staff and consultants.

Awardees will retain
custody of and have primary rights to the data and software developed under
these awards, subject to Government rights of access consistent with current
HHS, PHS, and NIH policies.

2.
A.2. NIH Responsibilities

An NIH Project
Scientist will have substantial programmatic involvement that is above and
beyond the normal stewardship role in awards, as described below.

With the LDT, assisting in the development of a
project milestone plan at the outset of the project.

Providing a perspective on the priorities of the
NIH Blueprint for Neuroscience Research and BPN.

Facilitating collaboration between the awardee,
NIH contracted consultants and service providers.

Enhancing the project progress by providing
access to various NIH resources when appropriate.

Providing technical assistance, advice and
coordination to the project, although the dominant role and responsibility for
the activities funded by the U01 resides with the awardee.

Coordinating testing of compounds under BPN
contracts.

Providing data from the BPN contractors to the
LDT and project PI.

Coordinating reports and presentations of project
progress to the BPN Steering Committee.

Serving as scientific liaison between the
awardee, other NIH program staff, and the BPN Project Team.

Reporting periodically on the progress of the project
to the BPN Project Team.

Additionally, an agency
program official or IC program director will be responsible for the normal
scientific and programmatic stewardship of the award and will be named in the
award notice.

2.A.3.
Collaborative Responsibilities

Project Lead Development
Team (LDT): The LDT will be co-chaired by the PI and an NIH-contracted drug
development consultant and will include additional members from the PI’s group,
consultants and NIH staff. This team will collaboratively set strategic
direction and guide the work flow for the project on an ongoing basis. The LDT
will meet every two weeks via teleconference to analyze and interpret data from
the PI and contracted laboratories and to formulate the subsequent experimental
plan. The team will produce progress reports for evaluation by the BPN Steering
Committee and BPN Project Team as needed.

BPN Steering Committee:
The Steering Committee will be responsible for reviewing and evaluating the
progress of the BPN projects in meeting their milestones and goals, and making
recommendations about the progress and directions of the BPN and individual
projects to the BPN Project Team. The Steering Committee will be composed of
6-8 senior non-federal scientists who are not directly involved in the
activities of the BPN. The BPN Project Team will appoint members to the
Steering Committee. The BPN Program Officers, Project Scientists and BPN
Project Team members may attend the Steering Committee meetings as non-voting
participants.

The BPN Steering Committee
will have the following involvement:

The BPN Steering
Committee will meet in person at least once a year and by conference call
quarterly. During part of the face-to-face meetings, there will be individual
meetings with the project PIs for presenting project progress and outcomes.

The Steering
Committee will review progress of the BPN and the individual projects and make
recommendations for improving program or project performance.

Based on progress of individual projects, the
Steering Committee will assess whether sufficient progress is being made toward
accomplishment of milestones and make recommendations to the BPN Project Team
about allocation of funding and resources within the network.

2.A.4.
Dispute Resolution Process

Any disagreements that
may arise in scientific or programmatic matters (within the scope of the award)
between award recipients and the NIH may be brought to Dispute Resolution. A
Dispute Resolution Panel composed of three members will be convened. It will have
three members: a designee of the Steering Committee chosen without NIH staff
voting, one NIH designee, and a third designee with expertise in the relevant
area who is chosen by the other two; in the case of individual disagreement,
the first member may be chosen by the individual awardee. This special dispute
resolution procedure does not alter the awardee's right to appeal an adverse
action that is otherwise appealable in accordance with PHS regulations 42 CFR
Part 50, Subpart D and HHS regulations 45 CFR Part 16.

A
final progress report, invention statement, and Financial Status Report are
required when an award is relinquished when a recipient changes institutions or
when an award is terminated.

Section
VII. Agency Contacts

We encourage
your inquiries concerning this funding opportunity and welcome the opportunity
to answer questions from potential applicants. Inquiries may fall into three
areas: scientific/research, peer review, and financial or grants management
issues:

Human
Subjects Protection:Federal
regulations (45CFR46) require that applications and proposals involving human
subjects must be evaluated with reference to the risks to the subjects, the
adequacy of protection against these risks, the potential benefits of the
research to the subjects and others, and the importance of the knowledge gained
or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and
Safety Monitoring Plan:Data and safety
monitoring is required for all types of clinical trials, including physiologic
toxicity and dose-finding studies (phase I); efficacy studies (Phase II);
efficacy, effectiveness and comparative trials (Phase III). Monitoring should
be commensurate with risk. The establishment of data and safety monitoring
boards (DSMBs) is required for multi-site clinical trials involving
interventions that entail potential risks to the participants (NIH Policy for
Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing
Research Data:Investigators
submitting an NIH application seeking $500,000 or more in direct costs in any
single year are expected to include a plan for data sharing or state why this
is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators
should seek guidance from their institutions, on issues related to
institutional policies and local IRB rules, as well as local, State and Federal
laws and regulations, including the Privacy Rule.

Policy
for Genome-Wide Association Studies (GWAS):NIH is interested in advancing genome-wide association
studies (GWAS) to identify common genetic factors that influence health and
disease through a centralized GWAS data repository. For the purposes of this
policy, a genome-wide association study is defined as any study of genetic
variation across the entire human genome that is designed to identify genetic
associations with observable traits (such as blood pressure or weight), or the
presence or absence of a disease or condition. All applications, regardless of
the amount requested, proposing a genome-wide association study are expected to
provide a plan for submission of GWAS data to the NIH-designated GWAS data
repository, or provide an appropriate explanation why submission to the
repository is not possible. Data repository management (submission and access)
is governed by the Policy for Sharing of Data Obtained in NIH Supported or
Conducted Genome-Wide Association Studies, NIH
Guide NOT-OD-07-088. For additional information,
see http://grants.nih.gov/grants/gwas/

Access
to Research Data through the Freedom of Information Act:The Office of
Management and Budget (OMB) Circular A-110 has been revised to provide access
to research data through the Freedom of Information Act (FOIA) under some
circumstances. Data that are (1) first produced in a project that is supported
in whole or in part with Federal funds and (2) cited publicly and officially by
a Federal agency in support of an action that has the force and effect of law
(i.e., a regulation) may be accessed through FOIA. It is important for
applicants to understand the basic scope of this amendment. NIH has provided
guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to
place data collected under this funding opportunity in a public archive, which
can provide protections for the data and manage the distribution for an
indefinite period of time. If so, the application should include a description
of the archiving plan in the study design and include information about this in
the budget justification section of the application. In addition, applicants
should think about how to structure informed consent statements and other human
subjects procedures given the potential for wider use of data collected under
this award.

Sharing of Model
Organisms:NIH is committed to
support efforts that encourage sharing of important research resources
including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH
recognizes the rights of grantees and contractors to elect and retain title to
subject inventions developed with Federal funding pursuant to the Bayh Dole Act
(see the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm). All investigators
submitting an NIH application or contract proposal, beginning with the October
1, 2004 receipt date, are expected to include in the application/proposal a
description of a specific plan for sharing and distributing unique model
organism research resources generated using NIH funding or state why such
sharing is restricted or not possible. This will permit other researchers to
benefit from the resources developed with public funding. The inclusion of a
model organism sharing plan is not subject to a cost threshold in any year and
is expected to be included in all applications where the development of model
organisms is anticipated.

Inclusion of Women
And Minorities in Clinical Research:It is the policy of the
NIH that women and members of minority groups and their sub-populations must be
included in all NIH-supported clinical research projects unless a clear and
compelling justification is provided indicating that inclusion is inappropriate
with respect to the health of the subjects or the purpose of the research. This
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 103-43). All investigators proposing clinical research should read the
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the
updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy
incorporates: the use of an NIH definition of clinical research; updated racial
and ethnic categories in compliance with the new OMB standards; clarification
of language governing NIH-defined Phase III clinical trials consistent with the
new PHS Form 398; and updated roles and responsibilities of NIH staff and the
extramural community. The policy continues to require for all NIH-defined Phase
III clinical trials that: a) all applications or proposals and/or protocols
must provide a description of plans to conduct analyses, as appropriate, to
address differences by sex/gender and/or racial/ethnic groups, including
subgroups if applicable; and b) investigators must report annual accrual and
progress in conducting analyses, as appropriate, by sex/gender and/or
racial/ethnic group differences.

Inclusion of
Children as Participants in Clinical Research:The NIH maintains a
policy that children (i.e., individuals under the age of 21) must be included
in all clinical research, conducted or supported by the NIH, unless there are
scientific and ethical reasons not to include them.

Required Education
on the Protection of Human Subject Participants:NIH policy requires
education on the protection of human subject participants for all investigators
submitting NIH applications for research involving human subjects and
individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

NIH Public Access
Policy Requirement:In
accordance with the NIH Public Access Policy (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html)
investigators must submit or have submitted for them their final, peer-reviewed
manuscripts that arise from NIH funds and are accepted for publication as of
April 7, 2008 to PubMed Central (http://www.pubmedcentral.nih.gov/), to be
made publicly available no later than 12 months after publication. As of May
27, 2008, investigators must include the PubMed Central reference number when
citing an article in NIH applications, proposals, and progress reports that
fall under the policy, and was authored or co-authored by the investigator or
arose from the investigator’s NIH award. For more information, see the Public
Access webpage at http://publicaccess.nih.gov/.

Standards
for Privacy of Individually Identifiable Health Information:The Department
of Health and Human Services (DHHS) issued final modification to the
"Standards for Privacy of Individually Identifiable Health
Information", the "Privacy Rule", on August 14, 2002. The
Privacy Rule is a federal regulation under the Health Insurance Portability and
Accountability Act (HIPAA) of 1996 that governs the protection of individually
identifiable health information, and is administered and enforced by the DHHS
Office for Civil Rights (OCR).

Decisions about applicability and implementation of
the Privacy Rule reside with the researcher and his/her institution. The OCR
website (http://www.hhs.gov/ocr/) provides information on the
Privacy Rule, including a complete Regulation Text and a set of decision tools
on "Am I a covered entity?" Information on the impact of the HIPAA
Privacy Rule on NIH processes involving the review, funding, and progress
monitoring of grants, cooperative agreements, and research contracts can be found
at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH
Grant Applications or Appendices:
All
applications and proposals for NIH funding must be self-contained within
specified page limitations. For publications listed in the appendix and/or
Progress report, internet addresses (URLs) must be used for publicly accessible on-line journal articles. Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide
any other information necessary for the review because reviewers are
under no obligation to view the Internet sites. Furthermore, we caution
reviewers that their anonymity may be compromised when they directly access an
Internet site.

Healthy
People 2010:The Public
Health Service (PHS) is committed to achieving the health promotion and disease
prevention objectives of "Healthy People 2010," a PHS-led national
activity for setting priority areas. This FOA is related to one or more of the
priority areas. Potential applicants may obtain a copy of "Healthy People
2010" at http://www.health.gov/healthypeople.

Authority and
Regulations:This
program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive
Order 12372. Awards are made under the authorization of Sections 301 and 405 of
the Public Health Service Act as amended (42 USC 241 and 284) and under Federal
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the
terms and conditions, cost principles, and other considerations described in
the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly
encourages all grant recipients to provide a smoke-free workplace and
discourage the use of all tobacco products. In addition, Public Law 103-227,
the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in
some cases, any portion of a facility) in which regular or routine education,
library, day care, health care, or early childhood development services are
provided to children. This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.

Loan
Repayment Programs:NIH encourages
applications for educational loan repayment from qualified health professionals
who have made a commitment to pursue a research career involving clinical,
pediatric, contraception, infertility, and health disparities related areas.
The LRP is an important component of NIH's efforts to recruit and retain the
next generation of researchers by providing the means for developing a research
career unfettered by the burden of student loan debt. Note that an NIH grant is
not required for eligibility and concurrent career award and LRP applications
are encouraged. The periods of career award and LRP award may overlap providing
the LRP recipient with the required commitment of time and effort, as LRP
awardees must commit at least 50% of their time (at least 20 hours per week
based on a 40 hour week) for two years to the research. For further
information, please see: http://www.lrp.nih.gov.